Methods using desmopressin acetate in orodispersible form

ABSTRACT

Described are orodispersible solid dosage forms of desmopressin or a pharmaceutically acceptable salt thereof useful for treating diseases or conditions such as incontinence, primary nocturnal enuresis (PNE), nocturia, and central diabetes insipidus. The dosage forms disintegrate in the mouth within 10 seconds and provide good desmopressin bioavailability.

THIS INVENTION relates to pharmaceutical formulations, to methods ofmaking them and to their use in the treatment and prophylaxis ofdiseases in mammals, particularly humans.

Desmopressin (1-desamino-8-D-arginine vasopressin, DDAVP) is an analogueof vasopressin having high antidiuretic activity. It is commerciallyavailable as the acetate salt both in tablet form and as a nasal spray,and is commonly prescribed for voiding postponement, incontinence,primary nocturnal enuresis (PNE) and nocturia, among other indications,including central diabetes insipidus.

While existing formulations of desmopressin have met the needs ofpatients, there is still a need for improvement. Tablets are oftenpreferred by patients because of their ease of use, discretion and thelack of uncertainty of correct administration. However, tabletsgenerally need to be taken with a glass of water or other drink, whichis a problem as fluid intake need to be restricted in connection withdesmopressin treatment, and the message to the patient is much clearerwhen there is no water intake at all. Furthermore the bioavailability ofdesmopressin when taken by tablet is about 0.1% when compared tointravenous injection, a figure which clearly leaves room forimprovement.

Intranasal administration leads to higher bioavailability, but is lesspreferred by patients. Further, intranasal administration may adverselyaffect the cilia, such that viruses and bacteria may more readily passinto the mucosa.

Sublingual formulations of desmopressin have previously been proposed.Grossman et al., Br. Med. J. 1215 (17 May 1980) reported administrationof desmopressin in a sublingual lozenge of unspecified composition. Inthe same year, Laczi et al., Int. J. Clin. Pharm. Ther. Tox. 18 (12)63-68 (1980) reported administration of 30 μg desmopressin in 200 mgsublingual tablets containing sucrose, potato starch, stearin, ethanol(as rectified spirit), white gelatin, distilled water and powderedcocoa. However, in WO-A-8502119 it is stated:

-   -   The so-called sublingual tablet is also objectionable since it        requires a relatively long dissolving time and is dependent on a        patient's saliva secretion. [WO-A-8502119, page 2, lines 4-6]

Fjellestad-Paulsen et al., Clin. Endocrinol. 38 177-82 (1993)administered a liquid nasal spray formulation of desmopressinsublingually, which avoided the problems noted above for the sublingualtablet. However, the authors reported that, following sublingualadministration of the liquid, no detectable desmopressin was found inthe blood.

It has now been discovered that desmopressin can be administered as asolid orodispersible dosage form which provides improved bioavailabilitycompared to conventional oral tablets of desmopressin.

According to a first aspect of the invention, there is provided anorodispersible pharmaceutical dosage form of desmopressin.

The desmopressin may be in the form of the free base or apharmaceutically or, where appropriate veterinarily, acceptable salt, orin any other pharmaceutically or veterinarily acceptable form. Theacetate salt is particularly preferred.

The formulation will typically be solid. It may disperse rapidly in themouth, for example within 10, 5, 2 seconds, or even within 1 second, inincreasing order of preference. Such formulations are termed‘orodispersible’. The formulation will typically comprise a suitablecarrier for this purpose, which will be pharmaceutically acceptable (orveterinarily acceptable in the case of administration to non-humananimals).

The daily dosage of desmopressin, measured as the free base, willgenerally be from 0.5 or 1 μg to 1 mg per dosage form. In one preferreddosage range, the dosage will typically range from 2 μg to 800 μg perdosage form and preferably from 10 μg to 600 μg. Relative low doses arealso specifically contemplated, for example from 0.5 μg to 75 μg,preferably 0.5 or 1 μg to 50 μg. When one dosage form per day isadministered, as is usual for PNE and nocturia, this will typically bethe dose per dosage form. When the daily dose is administered in two ormore dosages, as will typically be the case for central diabetesinsipidus, the amount of active compound per dosage form will be reducedaccordingly.

Other active ingredients, whether or not peptides, may also be present.

Pharmaceutical dosage forms of the present invention are adapted tosupply the active ingredient to the oral cavity. The active may beabsorbed across the sublingual mucosa, and/or otherwise from the oralcavity (e.g. across the buccal and/or gingival mucosa) and/or from thegastrointestinal tract for systemic distribution.

A variety of formulations are known which are suitable for deliveringother active ingredients for absorption from the oral cavity. Suchformulations may be useful in the present invention. Among them areintrabuccally disintegrating solid formulations or preparations whichcomprise the active ingredient, a sugar comprising lactose and/ormannitol and 0.12 to 1.2 w/w %, based on the solid components, of agarand which has a density of 400 mg/ml to 1,000 mg/ml and have asufficient strength for handling, which in practice may mean sufficientstrength to withstand removal from a blister packaging withoutdisintegrating. Such formulations, and how to make them, are disclosedin US-A-5466464, to which reference is made for further details.

In this embodiment of the invention, the sugar may be used in theformulation in an amount of at least 50 w/w %, preferably 80 w/w % ormore, more preferably 90 w/w % or more, based on the total solidcomponents, although it may vary depending on the quality and quantityof the active ingredient to be used.

Though types of agar are not particularly limited, those listed in theJapanese Pharmacopoeia may be used preferably. Examples of the listedagar include agar powders PS-7 and PS-8 (manufactured by Ina Shokuhin).

Agar may be used in an amount of from 0.12 to 1.2 w/w %, preferably from0.2 to 0.4 w/w %, based on the solid components.

In order to produce a formulation in accordance with this embodiment ofthe present invention, a sugar comprising lactose and/or mannitol issuspended in an aqueous agar solution, filled in a mould, solidifiedinto a jelly-like form and then dried. The aqueous agar solution mayhave a concentration of from 0.3 to 2.0%, preferably from 0.3 to 0.8%.The aqueous agar solution may be used in such an amount that theblending ratio of agar based on the solid components becomes 0.12 to 1.2w/w %, but preferably 40 to 60 w/w % of agar solution based on the solidcomponents.

Other formulations known for delivering active ingredients forabsorption from the oral cavity are the dosage forms disclosed in U.S.Pat. No. 6,024,981 and U.S. Pat. No. 6,221,392. They are hard,compressed, rapidly dissolvable dosage forms adapted for direct oraldosing comprising: an active ingredient and a matrix including anon-direct compression filter and a lubricant, said dosage form beingadapted to rapidly dissolve in the mouth of a patient and therebyliberate said active ingredient, and having a friability of about 2% orless when tested according to the U.S.P., said dosage form optionallyhaving a hardness of at least about 15 Newtons (N), preferably from15-50 N. U.S. Pat. No. 6,024,981 and US-A-6221392 disclose furtherdetails and characteristics of these dosage forms and how to make them.

Preferably, dosage forms in accordance with this embodiment of theinvention dissolve in about 90 seconds or less (preferably 60 seconds orless and most preferably 45 seconds or less) in the patient's mouth. Itis also often desirable that the dosage form include at least oneparticle. The particle would be the active ingredient and a protectivematerial. These particles can include rapid release particles and orsustained release particles.

In a particularly preferred formulation in accordance with thisembodiment of the present invention there is provided a hard,compressed, rapidly dissolving tablet adapted for direct oral dosing.The tablet includes particles made of an active ingredient and aprotective material. These particles are provided in an amount ofbetween about 0.01 and about 75% by weight based on the weight of thetablet. The tablet also includes a matrix made from a non-directcompression filler, a wicking agent, and a hydrophobic lubricant. Thetablet matrix comprises at least about 60% rapidly water solubleingredients based on the total weight of the matrix material. The tablethas a hardness of between about 15 and about 50 Newtons, a friability ofless than 2% when measured by U.S.P. and is adapted to dissolvespontaneously in the mouth of a patient in less than about 60 secondsand thereby liberate said particles and be capable of being stored inbulk.

A very fine grained or powdered sugar known as a non-direct compressionsugar may be used as a filler in the matrix of this embodiment thepresent invention. This material, in part because of its chemicalcomposition and in part because of its fine particle size, will dissolvereadily in the mouth in a matter of seconds once it is wetted by saliva.Not only does this mean that it can contribute to the speed at which thedosage form will dissolve, it also means that while the patient isholding the dissolving dosage form in his or her mouth, the filler willnot contribute a “gritty” or “sandy” texture thus adversely affectingthe organoleptic sensation of taking the dosage form. In contrast,direct compression versions of the same sugar are usually granulated andtreated to make them larger and better for compaction. While thesesugars are water soluble, they may not be solubilised quickly enough. Asa result, they can contribute to the gritty or sandy texture of thedosage form as it dissolves. Dissolution time in the mouth can bemeasured by observing the dissolution time of the tablet in water atabout 37° C. The tablet is immersed in the water without forcibleagitation or with minimal agitation. The dissolution time is the timefrom immersion to substantially complete dissolution of the rapidlywater soluble ingredients of the tablet as determined by visualobservation.

Particularly preferred fillers, in accordance with the present inventionare non-direct compression sugars and sugar alcohols which meet thespecifications discussed above. Such sugars and sugar alcohols include,without limitation, dextrose, mannitol, sorbitol, lactose and sucrose.Of course, dextrose, for example, can exist as either a directcompression sugar, i.e., a sugar which has been modified to increase itscompressibility, or a non-direct compression sugar.

Generally, the balance of the formulation can be matrix. Thus thepercentage of filler can approach 100%. However, generally, the amountof non-direct compression filler useful in accordance with the presentinvention ranges from about 25 to about 95%, preferably between about 50and about 95% and more preferably from about 60 to about 95%.

The amount of lubricant used can generally range from between about 1 toabout 2.5% by weight, and more preferably between about 1.5 to about 2%by weight. Hydrophobic lubricants useful in accordance with the presentinvention include alkaline stearates, stearic acid, mineral andvegetable oils, glyceryl behenate and sodium stearyl fumarate.Hydrophilic lubricants can also be used.

Protective materials useful in accordance with this embodiment of thepresent invention may include any of the polymers conventionallyutilized in the formation of microparticles, matrix-type microparticlesand microcapsules. Among these are cellulosic materials such asnaturally occurring cellulose and synthetic cellulose derivatives;acrylic polymers and vinyl polymers. Other simple polymers includeproteinaceous materials such as gelatin, polypeptides and natural andsynthetic shellacs and waxes. Protective polymers may also includeethylcellulose, methylcellulose, carboxymethyl cellulose and acrylicresin material sold under the registered trade mark EUDRAGIT by RhonePharma GmbH of Weiterstadt, Germany.

In addition to the ingredients previously discussed, the matrix may alsoinclude wicking agents, non-effervescent disintegrants and effervescentdisintegrants. Wicking agents are compositions which are capable ofdrawing water up into the dosage form. They help transport moisture intothe interior of the dosage form. In that way the dosage form candissolve from the inside, as well as from the outside.

Any chemical which can function to transport moisture as discussed abovecan be considered a wicking agent. Wicking agents include a number oftraditional non-effervescent disintegration agents. These include, forexample, microcrystalline cellulose (AVICEL PH 200, AVICEL PH 101),Ac-Di-Sol (Croscarmelose Sodium) and PVP-XL (a crosslinkedpolyvinylpyrrolidone); starches and modified starches, polymers, and gumsuch as arabic and xanthan. Hydroxyalkyl cellulose such ashydroxymethylcellulose, hydroxypropylcellulose andhydroxyopropylmethylcellulose, as well as compounds such as carbopol maybe used as well.

The conventional range of non-effervescent disintegrant agents used inconventional tablets can be as high as 20%. However, generally, theamount of disintegration agent used ranges from between about 2 andabout 5%, according to the Handbook of Pharmaceutical Excipients.

In accordance with this embodiment of the present invention, the amountof wicking agents used may range from between 2 to about 12% andpreferably from between 2 to about 5%.

It is also possible, of course, to include non-effervescentdisintegrants which may not act to wick moisture, if desirable. Ineither event, it is preferable to use either rapidly water soluble,non-effervescent disintegrants or wicking agents and/or to minimize theuse of generally non-water soluble wicking agents or non-effervescentdisintegrants. Non-rapidly dissolvable, non-rapidly water solubleelements if used in sufficient quantity, can adversely affect theorganoleptic properties of the tablets as they dissolve within the mouthand therefore should be minimized. Of course, wicking agents ornon-effervescent disintegrants which are rapidly water soluble asdiscussed herein can be used in greater quantity and they will not addto the grittiness of the formulation during dissolution. Preferredwicking agents in accordance with the present invention includecrosslinked PVP, although, the amounts of these must be controlled asthey are not rapidly water soluble.

In addition, it may be desirable to use an effervescent couple, incombination with the other recited ingredients to improve thedisintegration profile, the organoleptic properties of the material andthe like. Preferably, the effervescent couple is provided in an amountof between about 0.5 and about 50%, and more preferably, between about 3and about 15% by weight, based on the weight of the finished tablet. Itis particularly preferred that sufficient effervescent material beprovided such that the evolved gas is less than about 30 cm, uponexposure to an aqueous environment.

The term “effervescent couple” includes compounds which evolve gas. Thepreferred effervescent couple evolve gas by means of a chemical reactionwhich takes place upon exposure of the effervescent disintegrationcouple to water and/or to saliva in the mouth.

This reaction is most often the result of the reaction of a soluble acidsource and an alkali monohydrogencarbonate or other carbonate source.The reaction of these two general compounds produces carbon dioxide gasupon contact with water or saliva. Such water-activated materials mustbe kept in a generally anhydrous state and with little or no absorbedmoisture or in a stable hydrated form, since exposure to water willprematurely disintegrate the tablet. The acid sources may be any whichare safe for human consumption and may generally include food acids,acid and hydrite antacids such as, for example: citric, tartaric, malic,fumaric, adipic, and succinics. Carbonate sources include dry solidcarbonate and bicarbonate salt such as, preferably, sodium bicarbonate,sodium carbonate, potassium bicarbonate and potassium carbonate,magnesium carbonate and the like. Reactants which evolve oxygen or othergasses and which are safe for human consumption are also included.

In the case of the orally dissolvable tablets in accordance with thepresent invention, it is preferred that both the amount and the type ofdisintegration agent, either effervescent or non-effervescent, or thecombination thereof be provided sufficient in a controlled amount suchthat the tablet provides a pleasant organoleptic sensation in the mouthof the patient. In some instances, the patient should be able toperceive a distinct sensation of fizzing or bubbling as the tabletdisintegrates in the mouth. In general, the total amount of wickingagents, non-effervescent disintegrants and effervescent disintegrantsshould range from 0-50%. However, it should be emphasized that theformulations of the present invention will dissolve rapidly andtherefore, the need for disintegrating agents is minimal. As illustratedin the examples, appropriate hardness, friability and dissolution timescan be obtained even without effervescent disintegrants or highquantities of wicking agents.

The use of a non-direct compression filler eliminates the need for manyconventional processing steps such as granulation and/or the need topurchase more expensive pre-granulated, compressible fillers. At thesame time, the resulting dosage form is a balance of performance andstability. It is robust enough to be conventionally produced usingdirect compression. It is robust enough to be stored or packaged inbulk. Yet, it rapidly dissolves in the mouth while minimizing theunpleasant feel of conventional disintegrating tablets to the extentpossible.

Formulations in accordance with this embodiment of the invention may bemade by a method including the steps of:

(a) forming a mixture including an active ingredient and a matrixincluding a non-direct compression filler and a lubricant;

(b) compressing the mixture to form a plurality of hard, compressed,rapidly disintegrable dosage forms including the active ingredientdistributed in the orally dissolvable matrix; and optionally

(c) storing the dosage forms in bulk prior to packaging. In a preferredembodiment, the dosage forms are then packaged in a lumen of a packagesuch that there is at least one per package. In a preferred particularlypreferred embodiment, the dosage forms are then packaged in a lumen of apackage such that there more than one per package. Direct compression isthe preferred method of forming the dosage forms.

Other formulations known for delivering active ingredients forabsorption from the oral cavity are the dosage forms disclosed in U.S.Pat. No. 6,200,604, which comprise an orally administrable medicament incombination with an effervescent agent used as penetration enhancer toinfluence the permeability of the medicament across the buccal,sublingual, and gingival mucosa. In the context of the presentinvention, the medicament is desmopressin, which is administered in someembodiments across the sublingual mucosa. In the formulations of thisembodiment of the invention, effervescent agents can be used alone or incombination with other penetration enhancers, which leads to an increasein the rate and extent of oral absorption of an active drug.

Formulations or dosage forms in accordance with this embodiment of theinvention should include an amount of an effervescent agent effective toaid in penetration of the drug across the oral mucosa. Preferably, theeffervescent is provided in an amount of between about 5% and about 95%by weight, based on the weight of the finished tablet, and morepreferably in an amount of between about 30% and about 80% by weight. Itis particularly preferred that sufficient effervescent material beprovided such that the evolved gas is more than about 5 cm³ but lessthan about 30 cm³, upon exposure of the tablet to an aqueousenvironment.

The term “effervescent agent” includes compounds which evolve gas. Thepreferred effervescent agents evolve gas by means of a chemical reactionwhich takes place upon exposure of the effervescent agent (aneffervescent couple) to water and/or to saliva in the mouth. Thisreaction is most often the result of the reaction of a soluble acidsource and a source of carbon dioxide such as an alkaline carbonate orbicarbonate. The reaction of these two general compounds produces carbondioxide gas upon contact with water or saliva. Such water-activatedmaterials must be kept in a generally anhydrous state and with little orno absorbed moisture or in a stable hydrated form, since exposure towater will prematurely disintegrate the tablet. The acid sources may beany which are safe for human consumption and may generally include foodacids, acid and hydrite antacids such as, for example: citric, tartaric,amalic, fumeric, adipic, and succinics. Carbonate sources include drysolid carbonate and bicarbonate salt such as, preferably, sodiumbicarbonate, sodium carbonate, potassium bicarbonate and potassiumcarbonate, magnesium carbonate and the like. Reactants which evolveoxygen or other gasses and which are safe for human consumption are alsoincluded.

The effervescent agent(s) useful in this embodiment of the presentinvention is not always based upon a reaction which forms carbondioxide. Reactants which evolve oxygen or other gasses which are safefor human consumption are also considered within the scope. Where theeffervescent agent includes two mutually reactive components, such as anacid source and a carbonate source, it is preferred that both componentsreact completely. Therefore, an equivalent ratio of components whichprovides for equal equivalents is preferred. For example, if the acidused is diprotic, then either twice the amount of a mono-reactivecarbonate base, or an equal amount of a di-reactive base should be usedfor complete neutralization to be realised. However, in otherembodiments of the present invention, the amount of either acid orcarbonate source may exceed the amount of the other component. This maybe useful to enhance taste and/or performance of a tablet containing anoverage of either component. In this case, it is acceptable that theadditional amount of either component may remain unreacted.

Such dosage forms may also include in amounts additional to thatrequired for effervescence a pH adjusting substance. For drugs that areweakly acidic or weakly basic, the pH of the aqueous environment caninfluence the relative concentrations of the ionised and unionised formsof the drug present in solution according to the Henderson-Hasselbachequation. The pH solutions in which an effervescent couple has dissolvedis slightly acidic due to the evolution of carbon dioxide. The pH of thelocal environment, e.g. saliva in immediate contact with the tablet andany drug that may have dissolved from it, may be adjusted byincorporating in the tablet a pH adjusting substances which permit therelative portions of the ionised and unionised forms of the drug to becontrolled. In this way, the present dosage forms can be optimised foreach specific drug. If the unionised drug is known or suspected to beabsorbed through the cell membrane (transcellular absorption) it wouldbe preferable to alter the pH of the local environment (within thelimits tolerable to the subject) to a level that favours the unionisedform of the drug. Conversely, if the ionised form is more readilydissolved the local environment should favour ionisation.

The aqueous solubility of the drug should preferably not be compromisedby the effervescent and pH adjusting substance, such that the dosageforms permit a sufficient concentration of the drug to be present in theunionised form. The percentage of the pH adjusting substance and/oreffervescent should therefore be adjusted depending on the drug.

Suitable pH adjusting substance for use in the present invention includeany weak acid or weak base in amounts additional to that required forthe effervescence or, preferably, any buffer system that is not harmfulto the oral mucosa. Suitable pH adjusting substance for use in thepresent invention include, but are not limited to, any of the acids orbases previously mentioned as effervescent compounds, disodium hydrogenphosphate, sodium dihydrogen phosphate and the equivalent potassiumsalt.

The dosage form of this embodiment of the invention preferably includesone or more other ingredients to enhance the absorption of thepharmaceutical ingredient across the oral mucosa and to improve thedisintegration profile and the organoleptic properties of the dosageform. For example, the area of contact between the dosage form and theoral mucosa, and the residence time of the dosage form in the oralcavity can be improved by including a bioadhesive polymer in this drugdelivery system. See, for example, Mechanistic Studies onEffervescent-Induced Permeability Enhancement by Jonathan Eichman(1997), which is incorporated by reference herein. Effervescence, due toits mucus stripping properties, would also enhance the residence time ofthe bioadhesive, thereby increasing the residence time for the drugabsorption. Non-limiting examples of bioadhesives used in the presentinvention include, for example, Carbopol 934 P, Na CMC, Methocel,Polycarbophil (Noveon AA-1), HPMC, Na alginate, Na Hyaluronate and othernatural or synthetic bioadhesives.

In addition to the effervescence-producing agents, a dosage formaccording to this embodiment of the present invention may also includesuitable non-effervescent disintegration agents. Non-limiting examplesof non-effervescent disintegration agents include: microcrystalline,cellulose, croscarmelose sodium, crospovidone, starches, corn starch,potato starch and modified starches thereof, sweeteners, clays, such asbentonite, alginates, gums such as agar, guar, locust bean, karaya,pectin and tragacanth. Disintegrants may comprise up to about 20 weightpercent and preferably between about 2 and about 10% of the total weightof the composition.

In addition to the particles in accordance with this embodiment of thepresent invention, the dosage forms may also include glidants,lubricants, binders, sweeteners, flavouring and colouring components.Any conventional sweetener or flavouring component may be used.Combinations of sweeteners, flavouring components, or sweeteners andflavouring components may likewise be used.

Examples of binders which can be used include acacia, tragacanth,gelatin, starch, cellulose materials such as methyl cellulose and sodiumcarboxy methyl cellulose, alginic acids and salts thereof, magnesiumaluminium silicate, polyethylene glycol, guar gum, polysaccharide acids,bentonites, sugars, invert sugars and the like. Binders may be used inan amount of up to 60 weight percent and preferably about 10 to about 40weight percent of the total composition.

Colouring agents may include titanium dioxide, and dyes suitable forfood such as those known as F.D.& C. dyes and natural coloring agentssuch as grape skin extract, beet red powder, beta-carotene, annato,carmine, turmeric, paprika, etc. The amount of colouring used may rangefrom about 0.1 to about 3.5 weight percent of the total composition.

Flavours incorporated in the composition may be chosen from syntheticflavours oils and flavouring aromatics and/or natural oils, extractsfrom plants, leaves, flowers, fruits and so forth and combinationsthereof. These may include cinnamon oil, oil of wintergreen, peppermintoils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaveoil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil.Also useful as flavours are vanilla, citrus oil, including lemon,orange, grape, lime and grapefruit, and fruit essences, including apple,pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot andso forth. Flavours which have been found to be particularly usefulinclude commercially available orange, grape, cherry and bubble gumflavours and mixtures thereof. The amount of flavouring may depend on anumber of factors, including the organoleptic effect desired. Flavoursmay be present in an amount ranging from about 0.05 to about 3 percentby weight based upon the weight of the composition. Particularlypreferred flavours are the grape and cherry flavours and citrus flavourssuch as orange.

One aspect of the invention provides a solid, oral tablet dosage formsuitable for sublingual administration. Excipient fillers can be used tofacilitate tableting. The filler desirably will also assist in the rapiddissolution of the dosage form in the mouth. Non-limiting examples ofsuitable fillers include: mannitol, dextrose, lactose, sucrose, andcalcium carbonate.

As described in U.S. Pat. No. 6,200,604, tablets can either bemanufactured by direct compression, wet granulation or any other tabletmanufacturing technique. The dosage form may be administered to a humanor other mammalian subject by placing the dosage form in the subject'smouth and holding it in the mouth, beneath the tongue (for sublingualadministration). The dosage form spontaneously begins to disintegratedue to the moisture in the mouth. The disintegration, and particularlythe effervescence, stimulates additional salivation which furtherenhances disintegration.

Although the above described formulations are within the scope of thepresent invention, the most preferred orodispersible solidpharmaceutical dosage forms according to the invention comprisedesmopressin and an open matrix network carrying the desmopressin, theopen matrix network being comprised of a water-soluble orwater-dispersible carrier material that is inert towards desmopressin.

Pharmaceutical dosage forms comprising open matrix networks are knownfrom GB-A-1548022, to which reference is made for further details.Pharmaceutical dosage forms of the invention can be rapidlydisintegrated by water. By “rapidly disintegrated” is meant that theshaped articles are disintegrated in water within 10 seconds. Preferablythe shaped article disintegrates (dissolves or disperses) within 5seconds or even two seconds or one second or less. The disintegrationtime is measured by a procedure analogous to the Disintegration Test forTablets, B.P. 1973. The procedure is described in GB-A-1548022 andoutlined below.

Apparatus

A glass or suitable plastic tube 80 to 100 mm long, with an internaldiameter of about 28 mm and an external diameter of 30 to 31 mm, andfitted at the lower end, so as to form a basket, with a disc ofrustproof wire gauze complying with the requirements for a No. 1.70sieve.

A glass cylinder with a flat base and an internal diameter of about 45mm containing water not less than 15 cm deep at a temperature between36° and 38° C.

The basket is suspended centrally in the cylinder in such a way that itcan be raised and lowered repeatedly in a uniform manner so that at thehighest position the gauze just breaks the surface of the water and atthe lowest position the upper rim of the basket just remains clear ofthe water.

Method

Place one shaped article in the basket and raise and lower it in such amanner that the complete up and down movement is repeated at a rateequivalent to thirty times a minute. The shaped articles aredisintegrated when no particle remains above the gauze which would notreadily pass through it. No such particle should remain after 10seconds.

By the term “open matrix network” there is meant a network ofwater-soluble or water-dispersible carrier material having intersticesdispersed throughout. The open matrix network of carrier material is ofgenerally low density. For example the density may be within the range10 to 200 mg/cc e.g. 10 to 100 mg/cc, preferably 30 to 60 mg/cc. Thedensity of the shaped article may be affected by the amount of activeingredient, or any other ingredients, incorporated into the article andmay be outside the above mentioned preferred limits for the density ofthe matrix network. The open matrix network which is similar instructure to a solid foam enables a liquid to enter the product throughthe interstices and permeate through the interior. Permeation by aqueousmedia exposes the carrier material of both the interior and exterior ofthe product to the action of the aqueous media whereby the network ofcarrier material is rapidly disintegrated. The open matrix structure isof a porous nature and enhances disintegration of the product ascompared with ordinary solid shaped pharmaceutical dosage forms such astablets, pills, capsules, suppositories and pessaries. Rapiddisintegration results in rapid release of the active ingredient carriedby the matrix.

The carrier material used in the product of the invention may be anywater-soluble or water-dispersible material that is pharmacologicallyacceptable or inert to the chemical and which is capable of forming arapidly disintegratable open matrix network. It is preferred to usewater-soluble material as the carrier since this results in the mostrapid disintegration of the matrix when the product is placed in anaqueous medium. A particularly advantageous carrier may be formed frompolypeptides such as gelatin, particularly gelatin which is particularlyhydrolysed, e.g. by heating in water. For example, the gelatin may bepartially hydrolysed by heating a solution of the gelatin in water, e.g.in an autoclave at about 120° C. for up to 2 hours, e.g. from about 5minutes to about 1 hour, preferably from about 30 minutes to about 1hour. The hydrolysed gelatin is preferably used at concentrations ofabout 1 to 6% or 8% weight/vol., most preferably at 2 to 4% e.g. about3%, or at 4 to 6% e.g. about 5%. As is apparent from the Examplesherein, these concentrations refer to the total formulation prior toremoval of the water for example by freeze drying.

Although mammalian derived gelatin may be used, it has an unpleasanttaste and thus necessitates the use of sweeteners and flavours to maskthe taste of the gelatin in addition to any sweeteners and flavourswhich may be required to mask the taste of the active ingredient.Moreover, the heating step necessary with the use of mammalian gelatinincreases processing times and incurs heating costs thereby increasingthe overall costs of the process. Therefore, the use of fish gelatin,especially non-gelling fish gelatin, is preferred, especially fordesmopressin. Reference is made to WO-A-0061117 for further details.

Other carrier materials may be used in place of partially hydrolysedgelatin or fish gelatin, for example polysaccharides such as hydrolyseddextran, dextrin and alginates (e.g. sodium alginate) or mixtures ofabove mentioned carriers with each other or with other carrier materialssuch as polyvinyl alcohol, polyvinylpyrrolidine or acacia. Modifiedstarch may also be used in place of gelatin, as described inWO-A-0044351, to which reference is made for further details.

Other carrier materials which may be present in addition to, or in somecases in place of, the above carriers include: gums such as tragacanth,xanthan, carageenan, and guar; mucilages including linseed mucilage andagar; polysaccharides and other carbohydrates such as pectin and starchand its derivatives, particularly soluble starch and dextrates; watersoluble cellulose derivatives, such as hydroxyethylmethyl cellulose,hydroxypropylmethyl cellulose and hydroxypropyl cellulose; and carbomer.

A filler may also be present. The filler desirably will also assist inthe rapid dissolution or dispersion of the dosage form in the mouth.Non-limiting examples of suitable fillers include sugars such asmannitol, dextrose, lactose, sucrose and sorbitol. The filler ispreferably used at concentrations of about 0 to 6% or 8% weight/vol.,most preferably at 2 to 4% e.g. about 3%, or at 4 to 6% e.g. about 5%.Again, these concentrations refer to the total formulation prior toremoval of the water for example by freeze drying.

Pharmaceutical dosage forms of the invention may be in the form ofshaped articles. They may incorporate ingredients in addition to theactive ingredient(s). For example the pharmaceutical dosage form of thepresent invention may incorporate pharmaceutically acceptable adjuvants.Such adjuvants include, for example, colouring agents, flavouringagents, preservatives (e.g. bacteriostatic agents), and the like. U.S.Pat. No. 5,188,825 teaches that water soluble active agents should bebonded to an ion exchange resin to form a substantially water insolubleactive agent/resin complex; although that teaching may be practised here(for which reference to U.S. Pat. No. 5,188,825 is made for furtherdetails), it has been found in the development of the present inventionthat water soluble peptides such as desmopressin may be formulated insolid dosage forms of the invention without the need for bonding to anion exchange resin. Such dosage forms may therefore be free of an ionexchange resin. For hydrophobic peptides, which desmopressin is not, asurfactant may be present, as taught in U.S. Pat. No. 5,827,541, towhich reference is made for further details. For peptides with anunpleasant taste (which desmopressin does not have), a lipid such as alecithin may be present to improve patient acceptability, as taught inU.S. Pat. No. 6,156,339, to which reference is made for further details.Other strategies for taste masking include conversion of a soluble saltto a less soluble salt or to the free base, as taught by U.S. Pat. No.5,738,875 and U.S. Pat. No. 5,837,287, and the use of a processdisclosed in U.S. Pat. No. 5,976,577 wherein, prior to freeze drying, asuspension of uncoated or coated coarse particles of thepharmaceutically active substance(s) in a carrier material is cooled toreduce the viscosity and minimize release of the active substance duringprocessing, as well as beyond the point of disintegration of the form inthe mouth, to minimise bad taste from the peptide; reference is made tothe cited patents for further details.

For insoluble or poorly soluble peptides having a large particle size,xanthan gum may be present, particularly when the carrier is formed fromgelatin, as the xanthan gum may act as a gelatin flocculating agent, asdisclosed in U.S. Pat. No. 5,631,023, to which reference is made forfurther details.

As taught by WO-A-9323017 one or more amino acids having from about 2 to12 carbon atoms may be present, when the matrix is selected from thegroup consisting of gelatin, pectin, soy fibre protein and mixturesthereof. In this formulation the preferred amino acid is glycine, whilethe preferred matrix forming agent is gelatin and/or pectin; in aparticularly preferred embodiment, the dosage form additionallycomprises mannitol.

All excipients will be chosen to be pharmaceutically acceptable.

Pharmaceutical dosage forms of the present invention may be prepared bya process as described in GB-A-1548022, which comprises sublimingsolvent from a composition comprising the pharmaceutical substance and asolution of the carrier material in a solvent, the composition being inthe solid state in a mould.

The sublimation is preferably carried out by freeze drying a compositioncomprising the active ingredient and a solution of the carrier materialin a solvent. The composition may include additional ingredients, suchas those mentioned above. The solvent is preferably water but it maycontain a co-solvent (such as an alcohol e.g. tert-butyl alcohol) toimprove the solubility of the chemical. The composition may also containa surfactant e.g. Tween 80 (polyoxyethylene (20) sorbitan mono-oleate).The surfactant may help to prevent the freeze dried product sticking tothe surface of the mould. It may also aid in the dispersion of theactive ingredient.

The composition may contain a pH adjusting agent to adjust the pH of asolution from which the dosage form is prepared within the range of from3 to 6, preferably from 3.5 to 5.5, and most preferably from 4 to 5, forexample 4.5 or 4.8. Citric acid is a preferred pH adjusting agent, butothers including hydrochloric acid, malic acid can be used. Suchnon-volatile pH adjusting agents will not be removed by the freezedrying or other sublimation process and so may be present in the finalproduct.

The mould may comprise a series of cylindrical or other shapedepressions in it, each of a size corresponding to the desired size ofthe shaped article. Alternatively, the size of the depression in themould may be larger than the desired size of the article and after thecontents have been freeze dried the product can be cut into the desiredsize (for example thin wafers).

However, as described in GB-A-2111423, the mould is preferably adepression in a sheet of filmic material. The filmic material maycontain more than one depression. The filmic material may be similar tothat employed in conventional blister packs which are used for packagingoral contraceptive tablets and like medicament forms. For example thefilmic material may be made of thermoplastic material with thedepressions formed by thermoforming. The preferred filmic material is apolyvinyl chloride film. Laminates of filmic material may also be used.

In one embodiment the mould comprises a metal plate (e.g. an aluminiumplate) containing one or more depressions. In a preferred process usingsuch a mould, the mould is cooled with a cooling medium (e.g. liquidnitrogen or solid carbon dioxide). When the mould is cooled apredetermined amount of water containing the carrier material, theactive ingredient and any other desired ingredient is fed into thedepression(s). When the contents of the depression(s) are frozen themould is subjected to reduced pressure and, if desired, controlledapplication of heat to aid the sublimation. The pressure can be belowabout 4 mm. Hg; GB-A-1548022 teaches that employment of pressures ofbelow 0.3 mm Hg, for example 0.1 to 0.2 mm is preferred. The freezedried products may then be removed from the depressions in the mould andstored for future use, e.g. in airtight jars or other suitable storagecontainers. Alternatively, the freeze dried product may be enclosed byfilmic material as described in GB-A-2111423

A later developed process useful for making pharmaceutical dosage formsin accordance with the invention is described in GB-A-2111423, to whichreference is made for further details. The process comprises filling acomposition comprising a predetermined amount of active ingredient and asolution of partially hydrolysed gelatin into a mould, freezing thecomposition in the mould by passing gaseous cooling medium over themould and then subliming solvent from the frozen composition so as toproduce a network of partially hydrolysed gelatin carrying the activeingredient.

In order to help ensure an even thickness of product, the side wall orwalls of the mould may diverging outwards from the base and making anangle with the vertical of at least 5° at the surface of thecomposition, as described in GB-A-2119246 to which reference is made forfurther details.

Alternatively or in addition, pharmaceutical dosage forms of the presentinvention may be prepared by a process as described in GB-A-2114440which comprises freezing a composition comprising a solution in a firstsolvent of a water-soluble or water-dispersible carrier material that isinert towards the active ingredient, subliming the first solvent fromthe frozen composition so as to produce a product having a network ofcarrier material, adding to said product a solution or suspension of asecond non-aqueous solvent containing a predetermined amount of theactive ingredient and allowing or causing the second solvent toevaporate. Reference is made to GB-A-2114440 for further details.

Alternatively or in addition, pharmaceutical dosage forms of the presentinvention may be prepared by a process as described in GB-A-2111184,which comprises introducing the liquid medium in the form of dropletsbeneath the surface of a cooling liquid which is maintained at atemperature lower than the freezing point of the liquid medium, thecooling liquid being immiscible with, and inert with respect to, theliquid medium and having a density greater than that of both the liquidmedium and the resulting frozen particles such that as the liquiddroplets float upwards in the cooling liquid towards the surfacethereof, they are frozen to form spherical particles. The frozenspherical particles can be collected at or near the upper surface of thecooling liquid. Reference is made to GB-A-2111184 for further details.

Dosage forms in accordance with the invention have improvedbioavailability. They are intended to be taken orally, and are highlysuitable for that purpose. They disperse rapidly in the mouth, and mayfor example be placed under the tongue (sub-lingually), or they may beplaced on the tongue or against the cheek or gingiva.

According to a second aspect of the invention, there is provided adosage form as described above for use in medicine, particularly, forvoiding postponement, incontinence, primary nocturnal enuresis (PNE),nocturia and central diabetes insipidus.

The invention provides a method of postponing voiding, treating orpreventing incontinence, primary nocturnal enuresis (PNE), nocturiaand/or central diabetes insipidus, the method comprising administeringan effective and generally non-toxic amount of desmopressin to a subjectin an orodispersible pharmaceutical dosage form, for example in a dosageform as described above. Any other disease or condition treatable orpreventable by desmopressin may similarly be addressed by means of theinvention. The invention therefore extends to the use of desmopressin inthe manufacture of an orodispersible pharmaceutical formulation. Theinvention also extends to a pack comprising an orodispersiblepharmaceutical dosage form of desmopressin together with instructions toplace the dosage form in a patient's mouth. Encompassed within theinvention is also a method for preparing a packaged dosage form ofdesmopressin, the method comprising bringing into association anorodispersible pharmaceutical dosage form of desmopressin andinstructions to place the dosage form in a patient's mouth. Theinstructions may for example be printed on packaging encompassing thedosage form when sold or dispensed, or may be on a product informationleaflet or insert within the packaging.

Other peptides apart from desmopressin are formulatable in theformulations described above. The invention therefore extends to aorodispersible pharmaceutical dosage form of a pharmaceutically activepeptide.

According to a further aspect of the invention, there is provided asolid pharmaceutical dosage form, for example for oral administration,the dosage form comprising a pharmaceutically active peptide and an openmatrix network carrying the peptide, the open matrix network beingcomprised of a water-soluble or water-dispersible carrier material thatis inert towards the peptide.

Although oral vaccines made from fast dissolving dosage forms are knownfrom WO-A-9921579, there is no disclosure of pharmaceutically activepeptides retaining their activity after administration. The experimentalwork in WO-A-9921579 merely shows the presence in saliva of IgAantibodies to tetanus toxoid following the administration of tetanustoxoid by means of an adjuvanted fast dissolving dosage vaccineformulation. Formulations of the present invention are not vaccines anddo not include adjuvants.

Pharmaceutical dosage forms of this aspect of the invention contain apharmaceutically active peptide. Such peptides may be directly activeper se or they may have one or more active metabolites, i.e. they may beprodrugs for the primary or true active principle. The peptides may havefor example from 2 to 20, preferably from 5 to 15, amino acid residues(at least some of which may be D-isomers, although 1-isomers willgenerally be predominant). The peptides may be linear, branched orcyclic, and may include natural residues or substituents or residues orsubstituents not found in natural peptides or proteins either commonlyor at all. Pharmaceutically acceptable salts, simple adducts andtautomers are included where appropriate.

Examples of peptides usefully formulated by means of the inventioninclude somatostatin and its analogues includingCyclo(MeAla-Tyr-D-Trp-Lys-Val-Phe) andCyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-GABA), enkephalins includingMet⁵-enkephalin and Leu⁵-enkephalin, oxytocin analogues such as atosiban(1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-oxytocin), GnRH analogues such astriptorelin (6-D-Trp-GnRH), leuprolide ([D-Leu⁶, Pro⁸-NHEt]-GnRH),degarelix(Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(L-Hydroorotyl)-D-4Aph(Cbm)-Leu-Ilys-Pro-D-Ala-NH₂,where 2Nal is 2-naphthylalanine, 4Cpa is 4-chlorophenylalanine, 3Pal is3-pyridylalanine, ILys is N(ε)-isopropyllysine, 4Aph is4-aminophenylalanine and Cbm is the carbamoyl group) and other GnRHantagonists disclosed in U.S. Pat. No. 5,925,730 and U.S. Pat. No.4,072,668, and vasopressin analogues such as desmopressin. It isparticularly preferred to formulate by means of the invention agonistsof naturally active peptides, such as those described above, sinceagonists may be active at lower doses than antagonists.

Dosage will be as determined by the physician or clinician, depending onthe nature of the peptide, the nature of the disease or condition beingtreated or prevented, and other factors.

The invention extends to the use of a peptide in the manufacture of adosage form as described above for treating or preventing a disease orcondition which is treatable or preventable by a peptide.

The invention also provides a method of treating or preventing a diseaseor condition which is treatable or preventable by a peptide, the methodcomprising administering an effective and generally non-toxic amount ofthe peptide to a subject in a dosage form as described above.

The contents of each of the documents referred to in this specificationare incorporated herein by reference to the fullest extent allowed bylaw.

Preferred features of each aspect of the invention, and where feasibleand appropriate each embodiment of each aspect of the invention, are asfor each other aspect or embodiment, mutatis mutandis. In particular, itis contemplated that aspects, features and embodiments of the inventiondescribed above specifically in relation to desmopressin are applicablealso to other peptides.

The invention will now be illustrated by the following examples.

EXAMPLE 1 200 μg Desmopressin Orodispersible Dosage Form

Spray-dried fish gelatin (4 g) and mannitol (3 g) are added to a glassbeaker. Purified water (93 g) is then added and solution effected bystirring using a magnetic follower. The pH is checked and adjusted to4.8 with citric acid as necessary.

A Gilson pipette can then be used to deliver 500 mg of this solutioninto each one of a series of pre-formed blister pockets having a pocketdiameter of about 16 mm. The blister laminate may comprise PVC coatedwith PVdC. The dosed units are then frozen at a temperature of −110° C.in a freeze tunnel with a residence time of 3.2 minutes and the frozenunits are then held in an upright freezer for a time greater than 1.5hours at a temperature of −25° C. (±5° C.). The units are thenfreeze-dried overnight with an initial shelf temperature of 10° C.rising to +20° C. at a pressure of 0.5 mbar. The units can be checkedfor moisture prior to unloading by the drying trace and by thepressurised moisture check.

In this way, following the general procedure given in Example 1 ofWO-A-0061117, a desmopressin orodispersible dosage form is preparedusing the following ingredients per unit dosage form:

Desmopressin (PolyPeptide Laboratories, Sweden) 200 μg   Mannitol EP/USP(Roquette, Mannitol 35) 15 mg Fish gelatin USNF/EP 20 mg Citric acid (ifnecessary) [pH adjusting agent] q.s. to pH 4.8 Purified water [Removedduring processing]

EXAMPLE 2 400 μg Desmopressin Orodispersible Dosage Form

The procedure of Example 1 herein is followed, except that the amount ofdesmopressin per unit dosage form was 400 μg.

EXAMPLE 3 800 μg Desmopressin Orodispersible Dosage Form

The procedure of Example 1 herein is followed, except that the amount ofdesmopressin per unit dosage form was 800 μg.

EXAMPLE 4 200 μg Desmopressin Orodispersible Dosage Form

Following the general procedure given in Example 1 of WO-A-0061117, adesmopressin dosage form orodispersible dosage form was prepared usingthe following ingredients per unit dosage form:

Desmopressin (PolyPeptide Laboratories, Sweden) 200 μg   Mannitol EP/USP(Roquette, Mannitol 35)  6 mg Fish gelatin USNF/EP 10 mg Citric acid (ifnecessary) [pH adjusting agent] q.s. to pH 4.8 Purified water [Removedduring processing]

EXAMPLE 5 400 μg Desmopressin Orodispersible Dosage Form

The procedure of Example 4 herein was followed, except that the amountof desmopressin per unit dosage form was 400 μg.

EXAMPLE 6 800 μg Desmopressin Orodispersible Dosage Form

The procedure of Example 4 herein was followed, except that the amountof desmopressin per unit dosage form was 800 μg.

COMPARATIVE EXAMPLE 1 Desmopressin i.v. Solution

An injectable preparation of desmopressin was conventionally preparedusing the following ingredients:

Desmopressin (PolyPeptide Laboratories, Sweden) 4 mg Sodium chloride 9mg (National Corporation of Swedish Pharmacies, Sweden) Hydrochloricacid (1N) (Merck, Germany) q.s. to pH 4 Water for injection q.s. to 1 ml

COMPARATIVE EXAMPLE 2 200 μg Desmopressin Conventional Tablet

Using a conventional wet granulation process, tablets containing thefollowing ingredients were prepared:

Desmopressin (PolyPeptide Laboratories, Sweden) 200 μg Lactose(Pharmatose 150M, DMV, The Netherlands) 120 mg Potato starch (LyckebyAB, Sweden) 77 mg PVP (Kollidon 25, BASF, Germany) 1.8 mg Magnesiumstearate (Peter Greven, Germany) 1 mg Granulation Liquid (water,ethanol) [Removed during processing]

COMPARATIVE EXAMPLE 3 100 μg Desmopressin Conventional Tablet

The procedure of Comparative Example 2 was followed, except that theamount of desmopressin was 100 μg per tablet.

EXAMPLE 7 Bioavailability of Desmopressin Administered in Accordancewith Examples 4 to 6

Study Design

Twenty-four healthy non-smoking male volunteers were enrolled in thepresent study. The study was designed as a one-centre, open-labelled,randomised, balanced, 4-way cross-over phase I study. Each subject was,in a randomised order, administered sublingually desmopressin as a 200μg, 400 μg and 800 μg orodispersible dosage form (Examples 4, 5 and 6,respectively) and 2 μg as an i.v. bolus dose (Comparative Example 1).Between the doses there was a washout period of 72 hours. In order tostandardise the buccal mucosa before administration of theorodispersible tablet, the subjects were asked to avoid foods, chewinggum etc. Subjects were allowed to brush their teeth in the morningbefore dosing, but without toothpaste.

Blood Samples

Blood samples for plasma concentration of desmopressin were collectedaccording to the following schedule: pre-dose and 15, 30 and 45 min andat 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dosing. Afterintravenous administration additional blood samples were collected 5 and10 minutes post-dosing.

Assay

The concentration of desmopressin in plasma was determined by avalidated RIA method.

Pharmacokinetic Analysis

The concentration of desmopressin in plasma was analysed for theindividual volunteer in each administration group, by use ofnon-compartmental methods using the commercially available softwareWinNonlin™ Pro, ver. 3.2 (Pharsight Corporation, US). A plasmaconcentration value below limit of quantitation (LOQ) followed by valuesabove LOQ was set at ‘LOQ/2’ for the NCA analysis and for thedescriptive statistics on concentrations. Values below LOQ not followedby values above the LOQ are excluded from the NCA analysis, and set tozero in the descriptive statistics on concentrations.

Results of Pharmacokinetic Analysis

After i.v. administration the mean volume of distribution at steadystate (Vss) was 29.7 dm³. The mean clearance was calculated to be 8.5dm³/hr and the mean elimination half-life was determined to be 2.8hours. After oral administration of desmopressin maximum plasmaconcentrations were observed at 0.5-2.0 hours after dosing. The maximumplasma concentration was 14.25, 30.21 and 65.25 pg/ml after an oral doseof 200, 400 and 800 μg, respectively. After reaching the maximum valuedesmopressin was eliminated with a mean elimination half-life in therange of 2.8-3.0 hours. The bioavailability was determined to be 0.30%with at 95% confidence interval of 0.23-0.38%.

The pharmacokinetics of desmopressin is linear, when administered as theorodispersible dosage form of Example 4, 5 or 6.

COMPARATIVE EXAMPLE 4 Bioavailability of Desmopressin Administered inAccordance with Comparative Examples 2 and 3

Thirty six healthy male volunteers (Caucasian, Black and Hispanic) wereenrolled in this study, which was designed as an open label, singledose, 3-way crossover study. Each subject was, in a randomised order,administered 200 μg desmopressin as a single 200 μg tablet (ComparativeExample 2), 200 μg desmopressin as two 100 μg tablets (ComparativeExample 3) and 2 μg as an i.v. bolus dose (Comparative Example 1).

After i.v. administration the mean elimination half-life was determinedto be 2.24 hours. After oral administration of desmopressin maximumplasma concentrations were observed at 1.06 hours (2×100 μg) or 1.05hours (1×200 μg) after dosing. The maximum plasma concentration was 13.2and 15.0 μg/ml after an oral dose of 2×100 fig and 1×200 μg,respectively. The bioavailability was determined to be 0.13% (2×100 μg)or 0.16% (1×200 μg).

The invention claimed is:
 1. A method of treating a disease or conditionselected from the group consisting of incontinence, primary nocturnalenuresis (PNE), nocturia, and central diabetes insipidus, comprisingadministering to a subject in need thereof an effective and generallynon-toxic amount of desmopressin acetate in an orodispersible soliddosage form, wherein the dosage form (A) disintegrates in the mouthwithin 10 seconds and (B) comprises an amount of desmopressin acetate,measured as the free base, of from 0.5 μg to 75 μg, and wherein themethod results in a desmopressin bioavailability of from greater than0.1% to about 0.38%.
 2. The method of claim 1, wherein the methodresults in a desmopressin bioavailability of about 0.23% to about 0.38%.3. The method of claim 2, wherein the method results in a desmopressinbioavailability of about 0.30%.
 4. The method of claim 1, wherein thedosage form comprises an amount of desmopressin acetate, measured as thefree base, of from 1 μg to 50 μg.
 5. The method of claim 1, wherein thedosage form further comprises an open matrix network carrying thedesmopressin acetate, the open matrix network being comprised of awater-soluble or water-dispersible carrier material that is inerttowards desmopressin.
 6. The method of claim 5, wherein the open matrixnetwork comprises gelatin.
 7. The method of claim 6, wherein the gelatinis fish gelatin.
 8. The method of claim 7, wherein the fish gelatin isnon-gelling.
 9. The method of claim 1, wherein the dosage form furthercomprises citric acid.
 10. The method of claim 1, wherein the disease orcondition is primary nocturnal enuresis (PNE).
 11. The method of claim1, wherein the disease or condition is nocturia.
 12. The method of claim1, wherein the dosage form disintegrates in the mouth within 5 seconds.13. The method of claim 1, wherein the dosage form disintegrates in themouth within 2 seconds.
 14. The method of claim 1, wherein the dosageform is administered once per day.
 15. The method of claim 1, whereinthe dosage form is administered twice per day.
 16. The method of claim1, wherein the method results in a desmopressin bioavailability of fromgreater than 0.1% to 0.38%.
 17. The method of claim 1, wherein themethod results in a desmopressin bioavailability of from 0.23% to 0.38%.18. The method of claim 1, wherein the method results in a desmopressinbioavailability of 0.30%.